Download Addressing the challenges of poor solubility

Addressing the challenges of poor solubility: Rapid development and clinical
evaluation of a lipid based formulation to enhance oral bioavailability of
amuvatinib (MP-470)
P.D. Scholes1, J. McDermott1, J. Vertommen2, J-L Colin2, G Choy3, M Azab3, R Joshi3 and S. Redkar3
1Quotient
Bioresearch, Clinical Sciences, Mere Way, Ruddington Fields, Nottingham NG11 6JS, UK
2Capsugel, Product Development Center Strasbourg, France
3SuperGen Inc., Dublin CA, USA
Introduction
Clinical Conduct
Results (continued)
Physicochemical and biopharmaceutical properties of new chemical entities
(NCEs) are presenting increasing challenges to successful oral drug delivery.
It has been estimated that up to 70% of molecules in the industry pipeline
exhibit poor solubility characteristics1. The typical impact of sub-optimal
pharmacokinetic (PK) profiles arising from the First-in-Human (FIH) study will
be cost incursions and time delays whilst an optimal formulation is identified
for demonstrating Proof-of-Concept (PoC). It has been estimated that a
conventional development programme can take between 12-15 months and
cost more than $1.5 million to conduct2. A key contributor to these metrics is
the convoluted CMC process arising from conventional workstreams (Figure
1). We have previously described how an integrated GMP/GCP Translational
Pharmaceutics™ platform can reduce the time, cost and risk in the
optimisation of drug products in early development 3.
Clinical manufacturing and dosing were conducted within an integrated
GMP/GCP Translational Pharmaceutics platform at Quotient Bioresearch.
Formulation, analytical and manufacturing methodologies were transferred
under protocol into a GMP environment. A “full scale” batch size of 250g was
selected to cover the needs of the clinical study and quality control (QC)
testing. Briefly, the formulation was prepared by melting the lipidic excipients
and then adding the drug substance whilst mixing and homogenising at an
elevated temperature. Formulation equivalent to 30mg amuvatinib was then
filled into hard gelatin capsules. A process trial was conducted to confirm
homogeneity of the lipid suspension prior to encapsulation. Representative
batch release data and short-term (seven day) stability data were also
generated to support the Clinical Trial Application (CTA) submission.
Assay/impurities and dissolution parameters were assessed using suitably
qualified reverse phase HPLC and USP <711> (Apparatus A) methods
respectively.
GMP Technology Transfer
Representative batch release and short-term stability data were generated
demonstrating the suitability of the small scale GMP manufacturing process
(Table 1). Homogeneity of the product was verified through unit dose
sampling at top/middle/bottom locations of the mixing vessel (Overall RSD =
1%) (data not shown). These data were successfully included in the CTA to
support the “real-time” GMP manufacture and dosing of the clinical drug
product.
After regulatory and ethics approvals, the amuvatinib lipid-based formulation
was dosed as 3 x 30mg capsules in a two-way randomised crossover study in
the fasted state in 12 healthy volunteers, along with a 100mg reference
formulation (dry powder in capsule) with a 14 day wash-out period. Blood
samples were taken up to 48hr post-dose for PK analysis. The relative
bioavailability of the lipid-based formulation was assessed as the primary
study objective.
Results
Figure 1. Accelerating CMC development through a Translational
Pharmaceutics platform
Here we present data on amuvatinib (SuperGen Inc.), a novel multi-targeted
tyrosine kinase inhibitor specifically designed to be a potent inhibitor of
mutant c-Kit and PDGFRα. In early clinical studies amuvatinib had exhibited
solubility-limited exposure and a strong (positive) food effect. Through the use
of an integrated formulation development, manufacturing and clinical
evaluation programme, a lipid-based drug delivery system demonstrating
significantly improved oral bioavailability was effectively identified.
Formulation Development
A suspension-type, lipid-based formulation encapsulated in a Licaps® Drug
Delivery System capsule was developed for amuvatinib by Capsugel. The
lead formulation containing lipid-based excipients was identified from
experience-based in vitro screening experiments. These in vitro experiments
included dispersion testing, digestion testing and sedimentation testing using
a NIR Centrifugational Stability Analyzer (LUMiFuge®)4. The formulation work
was complimented by the development and validation of analytical methods
adapted to the lead lipid based formulation for in-process and quality control
purposes. A standard Capsugel formulation characterisation programme
including Differential Scanning Calorimetry (DSC) analysis, rheological
measurements and density measurements was performed on the lead lipid
formulation to characterise the formulation and define process parameters
using a Quality by Design (QbD) approach5.
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Formulation Development
A lead lipid-based suspension formulation was identified. Encapsulation
process simulation data for this lead formulation are shown in Figure 2 and
indicate that the formulation presents a viscosity within the recommended
range of 100 to 1000 mPas when dosed at 40°C using shear rates typically
generated in industrial filling pumps. After filling, the shear rate drops and the
viscosity of the formulation increases on cooling of the formulation in the
capsules. Further confirmation of process suitability and scaleability for
downstream development was demonstrated via the conduct of a mixing
device and addition sequence-testing study, a holding-time study and an
industrial pump simulation study (data not shown). Finally, a capsule batch
was successfully produced on Capsugel’s liquid capsule filling and sealing
(CFS) system to confirm the process feasibility.
Conclusions
Test
Specification
T = zero
T = 7 days
T = 28 days
Appearance
No visible residue on external
capsule surface, no cracks,
dents or physical defects on
capsules
Complies
Complies
Complies
Assay
90.0 – 110.0 %
103.4
103.4
102.5
Related
Substances
Unspecified = NMT 0.5%
Complies
Complies
Complies
Specified = NMT 2.0%
Complies
Complies
Complies
Total = NMT 5.0%
0.07%
0.07%
0.33%
Report results
15min = 30.3%
30min = 63.5%
45 min = 96.0%
60min = 103.1%
15min = 29.7%
30min = 77.1%
45 min = 99.2%
60min = 100.8%
15min = 23.7%
30min = 72.1%
45 min = 102.5%
60min = 101.7%
Early development strategies for the formulation optimisation of drug products
with specific drug delivery needs are enhanced via the integration of
pharmaceutical and clinical processes and facilities. Such approaches can
enhance the speed and outcome for the development of enabled formulations
to achieve satisfactory exposure or PK profiles in FIH and Phase I studies.
The development and use of a lipid-based formulation for amuvatinib, a BCS
Class II compound, encapsulated in a Licaps® Drug Delivery System, has
been shown to improve oral bioavailability significantly in comparison to a
reference dry powder in capsule formulation. In addition significant time
savings in the development process have been realised through the utilisation
of a combined GMP/GCP platform (Figure 4).
GMP Transfer
Clinical Study Conduct
Dissolution
(USP<711>
Apparatus 1
Clinical
Clinical data successfully demonstrated a six-fold increase in Cmax and a twofold increase in AUC from the amuvatinib lipid-based formulation compared to
control (dry powder in capsule) (Figure 3)6.
5
10
15
20
25
30
35
40
45
50
55
Time (weeks)
Figure 4. Overall study timelines for pharmaceutical
development and clinical assessment of a lipid-based
amuvatinib formulation.
Table 1. Representative batch release and stability data for
lead amuvatinib lipid formulation following storage at 25°C
The ability to manufacture product in a GMP environment close to the point of
clinical dosing reduces the stability data package required to support an
extended shelf-life, and can therefore enable both an expedited regulatory
submission and study conduct. This is complimented by the ability to reduce
the QC testing burden through the use of appropriate in-process controls and
the risk-based justification not to perform certain time-consuming finished
product characterisation, such as microbiological assessments. Firstsubject-first-dose can be achieved within five days of the onset of the GMP
manufacture of the dosage form.
References
Figure 3. Mean plasma concentration of Amuvatinib from
reference and lipid formulations time.
www.quotientbioresearch.com
Formulation Development
Regulatory Approval Process
0
1
Figure 2: Encapsulation process simulation for the lead formulation
Conventional
Process
Data
Study
Delivery
Timeline
Timelines
The application of an integrated workplan delivered significant time savings in
achieving these clinical data (Figure 4). Using Capsugel’s expertise a lead
formulation was identified in under 12 weeks. The clinical stage including
technology transfer, regulatory submissions, clinical manufacturing and
dosing was subsequently conducted in under 14 weeks at Quotient Clinical.
Hauss (2007), Advanced Drug Delivery Reviews, 59, 667-676
2 Quotient Bioresearch market research - unpublished
3 Scholes et al (2009), AAPS Poster #2869
4 Igonin at al (2009), AAPS, Poster #3329
5 Igonin et al (2007), AAPS Poster #3356
6 Joshi et al (2009), AACR Abstract #B209